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Purpose: Sarcoma encompasses a diverse group of cancers that are typically resistant to current therapies, including immune checkpoint blockade (ICB), and underlying mechanisms are poorly understood. The contexture of sarcomas limits generation of high-quality data using cutting-edge molecular profiling methods, such as single-cell RNA-sequencing, thus hampering progress in understanding these understudied cancers., Experimental Design: Here, we demonstrate feasibility of producing multimodal single-cell genomics and whole-genome sequencing data from frozen tissues, profiling 75,716 cell transcriptomes of five undifferentiated pleomorphic sarcoma and three intimal sarcoma samples, including paired specimens from two patients treated with ICB., Results: We find that genomic diversity decreases in patients with response to ICB, and, in unbiased analyses, identify cancer cell programs associated with therapy resistance. Although interactions of tumor-infiltrating T lymphocytes within the tumor ecosystem increase in ICB responders, clonal expansion of CD8+ T cells alone was insufficient to predict drug responses., Conclusions: This study provides a framework for studying rare tumors and identifies salient and treatment-associated cancer cell intrinsic and tumor microenvironmental features in sarcomas., (©2024 The Authors; Published by the American Association for Cancer Research.)

Some conditions known as temporomandibular disorders (TMDs) affect surrounding muscles and jaw joints. In dentistry, there has been discussion and research on the connection between TMDs and occlusion, which is how the upper and lower teeth meet. Although some dental experts have proposed a direct link between TMDs and occlusion, the specifics of this relationship are still unclear and have many facets. More particularly, the research facets of "occlusion" remain one of the most contentious subjects in TMDs. This abstract aims to provide an overview of TMDs and occlusion, summarizing the key points from the literature. The etiological factors contributing to the TMDs, including occlusal, psychological, and hormonal factors, are also analyzed. The second part of the article includes the concept of malocclusion, emphasizing its significance in masticatory function and overall health. Anterior open and posterior open bites and the potential influence of occlusal factors on TMDs are elucidated., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Monika et al.)

Objective: This study evaluated the effects of receiving glucose feedback from continuous glucose monitoring (CGM) by intermittent scanning (unblinded group), and CGM with masked feedback (blinded group) in the subsequent development of gestational diabetes mellitus (GDM)., Study Design: This was a prospective, single-center, pilot, randomized controlled trial including n  = 206 pregnant women in the first trimester of pregnancy with no prior diagnosis of type 1 or type 2 diabetes. The participants were randomized into the unblinded group or blinded group and wore the CGM in the first trimester of pregnancy (9-13 weeks), the second trimester of pregnancy (18-23 weeks), and late-second to early-third trimester (24-31 weeks). The primary outcome was GDM rate as diagnosed by the 75-g oral glucose tolerance test (OGTT) at 24 to 28 weeks., Results: Over 47 months, 206 pregnant women were enrolled at 9 to 13 weeks. The unblinded group had a higher prevalence of women who developed GDM (21.5 vs. 14.9%; p  > 0.05), compared to the blinded group. In the unblinded group compared to the blinded group, plasma glucose values were higher at 1 hour (median 7.7 [interquartile range {IQR}: 6.3-9.2] vs. 7.5 [6.3-8.7]) and 2 hours (6.3 [5.8-7.7] vs. 6.2 [5.3-7.2]), but lower at 0 hour (4.2 [4.0-4.5] vs. 4.3 [4.1-4.6]; p  > 0.05). All these differences were not statistically significant., Conclusion: Glucose feedback from CGM wear in the first to the third trimester of pregnancy without personalized patient education failed to alter GDM rate., Key Points: · Continuous glucose monitoring (CGM) is feasible for use in pregnant women.. · No significant difference in gestational diabetes rates with or without CGM feedback.. · Future clinical trials should incorporate CGM education and personalized guidance to enhance study outcomes.., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background Multidisciplinary simulation training in the management of acute obstetric emergencies has the potential to reduce both maternal and perinatal morbidity. It is a valuable tool that can be adapted for targeted audiences of different specialities at all experience levels from medical students to senior consultants. Methods In this study, pre- and post-course questionnaires of learners with varying levels of clinical experience from Obstetrics and Gynaecology (O&G), Anaesthesia, Neonatology, Emergency Medicine, midwifery, and nursing who undertook two simulation courses (namely the Combined Obstetrics Resuscitation Training course, CORE, and the CORE Lite), which comprised lectures and simulation drills with manikins and standardized patients, between 2015 and 2023 were compared. This also included a period when training was affected by the coronavirus disease 2019 (COVID-19) pandemic.  Results The results showed that both simulation courses increased confidence levels among all learners in the management of obstetric emergencies.  Pre-course, participants were most confident in the management of neonatal resuscitation and severe pre-eclampsia, followed by postpartum haemorrhage. They were least confident in the management of vaginal breech delivery, uterine inversion, and twin delivery. Post-course, participants were most confident in the management of neonatal resuscitation and shoulder dystocia, followed by postpartum haemorrhage. They were least confident in the management of uterine inversion and maternal sepsis, followed by vaginal breech delivery and twin delivery. Whilst we saw a huge improvement in confidence levels for all obstetric emergencies, the greatest improvement in confidence levels was noted in vaginal breech delivery ,  twin delivery ,  and uterine inversion. Conclusion The simulation courses were effective in improving the confidence in the management of obstetric emergencies. While it may be difficult to measure the improvement in clinical outcomes as a result of simulation courses alone, the increase in confidence levels of clinicians can be used as a surrogate in measuring their preparedness in facing these emergency scenarios., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Li et al.)

Introduction Iron deficiency anemia is associated with an increased risk of adverse maternal and perinatal outcomes. Intravenous iron preparation containing ferric carboxymaltose has been shown to be a safe and effective way of increasing hemoglobin (Hb) and mean corpuscular volume (MCV) levels and reducing the need for blood transfusion. In our center, it used to be given as an inpatient procedure because of the risks of potential drug reactions. In 2021, we initiated the administration of intravenous ferric carboxymaltose as an outpatient procedure. We compared the outcomes of patients between 2021 and 2023 after the initiation of outpatient administration of intravenous ferric carboxymaltose in 127 obstetric patients with iron deficiency anemia in the second and third trimesters. Methods In this study conducted in a large maternity unit in Singapore between 2021 to 2023, we compared the changes in maternal hematological parameters among obstetric patients with iron deficiency anemia presenting to the day care unit in the second or third trimester with a Hb level of <8 g/dl treated with a single dose of ferric carboxymaltose injection (Ferinject) against a control group who were referred for treatment but defaulted on and declined treatment. Results Ferric carboxymaltose significantly increased the Hb and MCV levels at delivery in obstetric patients with iron deficiency. The mean Hb at delivery was 10.8 g/dL in the case group compared to 8.8 g/dL in the control group. The percentage of patients with Hb ≥10.0 g/dL was 73.4% in the case group compared to 27.8% in the control group. The incidence of adverse side effects was low and mild (2/127; 1.6%). None of the patients received were hospitalized because of ferric carboxymaltose. Conclusion A single injection dose of ferric carboxymaltose as an outpatient antenatal procedure was easily administered and well tolerated. Obstetric patients with iron deficiency anemia who received intravenous ferric carboxymaltose had a significantly higher level of Hb than those who did not., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Li et al.)

Liver metastasis (LM) confers poor survival and therapy resistance across cancer types, but the mechanisms of liver-metastatic organotropism remain unknown. Here, through in vivo CRISPR-Cas9 screens, we found that Pip4k2c loss conferred LM but had no impact on lung metastasis or primary tumor growth. Pip4k2c-deficient cells were hypersensitized to insulin-mediated PI3K/AKT signaling and exploited the insulin-rich liver milieu for organ-specific metastasis. We observed concordant changes in PIP4K2C expression and distinct metabolic changes in 3,511 patient melanomas, including primary tumors, LMs and lung metastases. We found that systemic PI3K inhibition exacerbated LM burden in mice injected with Pip4k2c-deficient cancer cells through host-mediated increase in hepatic insulin levels; however, this circuit could be broken by concurrent administration of an SGLT2 inhibitor or feeding of a ketogenic diet. Thus, this work demonstrates a rare example of metastatic organotropism through co-optation of physiological metabolic cues and proposes therapeutic avenues to counteract these mechanisms., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Electromyography, commonly known as EMG, utilizes superficial or needle electrodes to record and analyze the fundamental electrical characteristics of skeletal muscles, determining whether the muscles are contracting. The motor unit, which consists of a collection of group muscle fibers and the motor neurons that govern them, is the structural basis of EMG. Three types of electrode are used in EMG which are needle electrode, fine wire electrode, and surface electrode. A significant amount of literature indicates that the correction of muscle function affects the relationships between teeth within the same jaw and between the jaws on opposing sides. The mechanism of action in myofunctional appliance therapy is linked to neuromuscular and skeletal adaptations resulting from altered function in the orofacial region. Both myofunctional therapy and orthodontics aim to address abnormal muscular behavior, restore abnormal muscle activity, and maintain proper alignment in various areas, including the lips, lower jaw, and tongue. This knowledge is essential for functions such as swallowing, speaking, chewing, and respiration as well as for minimizing incorrect movements and positioning. This article aims to describe the application of surface EMG as a diagnosis tool for assessing muscle activities in various orthodontic disorders, such as class II malocclusion open bite, crossbite, maxillary constriction, cleft lip and palate (CLP), and temporomandibular dysfunction, in patients. The electrodes used in EMG can be utilized to detect bioelectric activity in the muscles of the jaws and abnormalities in jaw movement. Analyzing EMG data is vital for obtaining a comprehensive understanding of the masticatory muscle system., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Tagore et al.)

Current methods for biomarker discovery and target identification in immuno-oncology rely on static snapshots of tumor immunity. To thoroughly characterize the temporal nature of antitumor immune responses, we developed a 34-parameter spectral flow cytometry panel and performed high-throughput analyses in critical contexts. We leveraged two distinct preclinical models that recapitulate cancer immunoediting (NPK-C1) and immune checkpoint blockade (ICB) response (MC38), respectively, and profiled multiple relevant tissues at and around key inflection points of immune surveillance and escape and/or ICB response. Machine learning-driven data analysis revealed a pattern of KLRG1 expression that uniquely identified intratumoral effector CD4 T cell populations that constitutively associate with tumor burden across tumor models, and are lost in tumors undergoing regression in response to ICB. Similarly, a Helios - KLRG1 + subset of tumor-infiltrating regulatory T cells was associated with tumor progression from immune equilibrium to escape and was also lost in tumors responding to ICB. Validation studies confirmed KLRG1 signatures in human tumor-infiltrating CD4 T cells associate with disease progression in renal cancer. These findings nominate KLRG1 + CD4 T cell populations as subsets for further investigation in cancer immunity and demonstrate the utility of longitudinal spectral flow profiling as an engine of dynamic biomarker discovery., Competing Interests: Competing interests: BI has received consulting fees from Volastra Therapeutics, Merck, AstraZeneca and Janssen Pharmaceuticals and has received research funding to Columbia University from Alkermes, Arcus Biosciences, Checkmate Pharmaceuticals, Compugen, Immunocore, and Synthekine. CGD is a coinventor on patents licensed from JHU to BMS and Janssen, has served as a paid consultant to AZ Medimmune, BMS, Pfizer, Roche, Sanofi Aventis, Genentech, Merck, and Janssen, has received sponsored research funding to his institution from BMS IIoN and Janssen, and is a current employee of Janssen., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To evaluate the effectiveness of tranexamic acid (TXA) in reducing blood loss during elective caesarean sections in women with and without risk factors for postpartum haemorrhage (PPH)., Design: A double-blind, randomised placebo-controlled trial., Setting: An academic tertiary referral centre in Singapore., Population: Multiethnic women aged 21 years or older undergoing elective caesarean section., Methods: Randomisation to intravenous TXA or normal saline (placebo) 10 minutes before skin incision., Main Outcome Measures: Calculated estimated blood loss (cEBL), derived from blood volume and haematocrit levels., Results: Between June 2020 and October 2021, 200 women were randomised to the placebo or TXA groups. Women who received prophylactic TXA had a significantly lower mean cEBL compared with those receiving placebo (adjusted mean difference -126.4 mL, 95% CI -243.7 to -9.1, p = 0.035). The effect was greatest in those at high risk for PPH, with a reduction in cEBL (mean difference -279.6 mL, 95% CI -454.8 to -104.3, p = 0.002) and a lower risk of cEBL ≥500 mL (risk ratio [RR] 0.54, 95% CI 0.36-0.83, p = 0.007) and cEBL ≥1000 mL (RR 0.44, 95% CI 0.20-0.98, p = 0.016). Subgroup analysis showed benefit for women with preoperative haemoglobin <10.5 g/dL (mean difference -281.9 mL, 95% CI -515.0 to -48.8, p = 0.019). There was no significant difference in need for additional medical or surgical interventions. There were no maternal or neonatal adverse outcomes., Conclusion: Prophylactic TXA should be considered in women with risk factors for PPH, and those most likely to benefit are those with preoperative haemoglobin <10.5 g/dL., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

While the functional effects of many recurrent cancer mutations have been characterized, the TCGA repository comprises more than 10M non-recurrent events, whose function is unknown. We propose that the context specific activity of transcription factor (TF) proteins-as measured by expression of their transcriptional targets-provides a sensitive and accurate reporter assay to assess the functional role of oncoprotein mutations. Analysis of differentially active TFs in samples harboring mutations of unknown significance-compared to established gain (GOF/hypermorph) or loss (LOF/hypomorph) of function-helped functionally characterize 577,866 individual mutational events across TCGA cohorts, including identification of mutations that are either neomorphic (gain of novel function) or phenocopy other mutations ( mutational mimicry ). Validation using mutation knock-in assays confirmed 15 out of 15 predicted gain and loss of function mutations and 15 of 20 predicted neomorphic mutations. This could help determine targeted therapy in patients with mutations of unknown significance in established oncoproteins.

Single-cell genomics enables dissection of tumor heterogeneity and molecular underpinnings of drug response at an unprecedented resolution 1-11 . However, broad clinical application of these methods remains challenging, due to several practical and preanalytical challenges that are incompatible with typical clinical care workflows, namely the need for relatively large, fresh tissue inputs. In the present study, we show that multimodal, single-nucleus (sn)RNA/T cell receptor (TCR) sequencing, spatial transcriptomics and whole-genome sequencing (WGS) are feasible from small, frozen tissues that approximate routinely collected clinical specimens (for example, core needle biopsies). Compared with data from sample-matched fresh tissue, we find a similar quality in the biological outputs of snRNA/TCR-seq data, while reducing artifactual signals and compositional biases introduced by fresh tissue processing. Profiling sequentially collected melanoma samples from a patient treated in the KEYNOTE-001 trial 12 , we resolved cellular, genomic, spatial and clonotype dynamics that represent molecular patterns of heterogeneous intralesional evolution during anti-programmed cell death protein 1 therapy. To demonstrate applicability to banked biospecimens of rare diseases 13 , we generated a single-cell atlas of uveal melanoma liver metastasis with matched WGS data. These results show that single-cell genomics from archival, clinical specimens is feasible and provides a framework for translating these methods more broadly to the clinical arena., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Codon usage of each genome is closely correlated with the abundance of tRNA isoacceptors. How codon usage bias is resolved by tRNA post-transcriptional modifications is largely unknown. Here we demonstrate that the N 1 -methylation of guanosine at position 37 (m 1 G37) on the 3'-side of the anticodon, while not directly responsible for reading of codons, is a neutralizer that resolves differential decoding of proline codons. A genome-wide suppressor screen of a non-viable Escherichia coli strain, lacking m 1 G37, identifies proS suppressor mutations, indicating a coupling of methylation with tRNA prolyl-aminoacylation that sets the limit of cell viability. Using these suppressors, where prolyl-aminoacylation is decoupled from tRNA methylation, we show that m 1 G37 neutralizes differential translation of proline codons by the major isoacceptor. Lack of m 1 G37 inactivates this neutralization and exposes the need for a minor isoacceptor for cell viability. This work has medical implications for bacterial species that exclusively use the major isoacceptor for survival., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Perinatal Palliative Care provides comprehensive and holistic care for expectant and new parents, who receive a diagnosis of life-limiting fetal condition and opt to continue pregnancy and care for their newborn infant. Aim: To develop a service providing individually tailored holistic care during pregnancy, birth, postnatal and bereavement period. Methods: Following a baseline survey of neonatologists and discussions with key stakeholders we launched the Perinatal Palliative service at the KK Women's and Children's hospital, Singapore in January 2017. The multidisciplinary team, led by a Palliative care specialist comprised of Obstetricians, Neonatologists, nurses and medical social workers. The Birth defect clinic referred parents with antenatally diagnosed 'Lethal' fetal conditions. The team checked the understanding and the decision making process of parents and initiated and finalized advance care plans. The service also embraced deserving postnatal referrals upon request. Results: A total of 41 cases were seen from January 2017 to December 2019. Of these, 26/41(63%) were referred antenatally and had completed advance care plans. 18/41 (44%) died during or shortly after birth and 10/41(24%) continue to survive and are supported by the community palliative team. During this time a workflow was formulated and modified based on parent and team feedback. Conclusion: Awareness of the service has increased over the years and a clear workflow has been formulated. Advance care plans are prepared and documented before birth so as to enable service teams on board to provide well timed pertinent care. Feedbacks from parents about this service were positive.

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX + CD8 + T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration., Competing Interests: Declaration of interests B.I. has received honoraria from consulting with Merck, Janssen Pharmaceuticals, Astra Zeneca, and Volastra Therapeutics. M.A.D. has been a consultant to Roche/Genentech, Array, Pfizer (New York, NY, United States of America), Novartis, BMS, GSK, Sanofi-Aventis (Bridgewater, NJ, United States of America), Vaccinex, Apexigen, EISAI, and ABM Therapeutics and he has been the PI of research grants to MD Anderson by Roche/Genentech (South San Francisco, CA, United States of America), GSK, Sanofi-Aventis, Merck, Myriad, and Oncothyreon. A.R. has received honoraria from consulting with CStone, Merck, and Vedanta, is or has been a member of the scientific advisory board and holds stock in Advaxis, Appia, Apricity, Arcus, Compugen, CytomX, Highlight, ImaginAb, ImmPact, ImmuneSensor, Inspirna, Isoplexis, Kite-Gilead, Lutris, MapKure, Merus, PACT, Pluto, RAPT, Synthekine, and Tango, has received research funding from Agilent (Santa Clara, CA, United States of America) and from Bristol-Myers Squibb through Stand Up to Cancer (SU2C), and patent royalties from Arsenal Bio. T.E. has acted as a consultant for Almiral Hermal, Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, and Sanofi. E.Z.M. is a consultant for Curio Bioscience. The other authors do not declare competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Red cell transfusion is expensive and not without risks. Despite the availability of transfusion guidelines, studies report a wide interhospital variation in transfusion rates. This retrospective cohort study was conducted to define the incidence of red cell transfusion in a multi-ethnic obstetric population and to evaluate current transfusion practice with regard to indications and appropriateness., Methods: All parturients who delivered a live or stillbirth in the period 2014-2015 and who received allogeneic blood transfusion during pregnancy and up to six weeks postnatally were identified. Their medical records were reviewed to extract the relevant demographic, obstetric and transfusion data. Descriptive analysis of data was performed using IBM SPSS Statistics software., Results: Out of 23,456 parturients who delivered in the study period, 760 were administered red cell transfusion, resulting in a transfusion rate of 3.2% or 32 in 1,000 maternities. A total of 1,675 red cell units were utilised in 863 transfusion episodes. Major indications for transfusion were anaemia in pregnancy (49.2%) and postpartum haemorrhage secondary to an atonic uterus. Transfusion was more frequently associated with caesarean than vaginal births (4.9% vs. 2.4%). About 14% of transfusions were initiated with pre-transfusion haemoglobin (Hb) ≥ 8.0 g/dL, whereas 37% of transfusions resulted in post-transfusion Hb > 9.0 g/dL., Conclusion: The incidence of red cell transfusion was 3.2% in a multiethnic obstetric population. Patient blood management strategies should focus on optimising antenatal anaemia, reducing blood loss during delivery and eliminating inappropriate transfusion., (Copyright: © Singapore Medical Association)

Engineered tissues can be used to model human pathophysiology and test the efficacy and safety of drugs. Yet, to model whole-body physiology and systemic diseases, engineered tissues with preserved phenotypes need to physiologically communicate. Here we report the development and applicability of a tissue-chip system in which matured human heart, liver, bone and skin tissue niches are linked by recirculating vascular flow to allow for the recapitulation of interdependent organ functions. Each tissue is cultured in its own optimized environment and is separated from the common vascular flow by a selectively permeable endothelial barrier. The interlinked tissues maintained their molecular, structural and functional phenotypes over 4 weeks of culture, recapitulated the pharmacokinetic and pharmacodynamic profiles of doxorubicin in humans, allowed for the identification of early miRNA biomarkers of cardiotoxicity, and increased the predictive values of clinically observed miRNA responses relative to tissues cultured in isolation and to fluidically interlinked tissues in the absence of endothelial barriers. Vascularly linked and phenotypically stable matured human tissues may facilitate the clinical applicability of tissue chips., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Pregnancy associated sleep disturbances is a common pregnancy-related complication which can lead to significant maternal distress and adverse pregnancy outcomes. Sleep quality can be affected by multiple factors and obesity has been recognized as one of them. Various previous studies have demonstrated poorer sleep quality during pregnancy. However, most studies included assessment at only one point of pregnancy. This prospective cohort study aimed to better evaluate the effect of pregnancy on the quality of sleep throughout the antenatal period and how BMI affects antenatal sleep., Methods: A total of 926 women were recruited before 14 weeks of gestation and followed throughout pregnancy. The Pittsburgh Sleep Quality Index questionnaire (PSQI) was employed to assess sleep quality in 4 antenatal visits throughout pregnancy. Their weight was also recorded at each visit., Results: The PSQI global score was higher towards the later part of pregnancy (6.4 to 8.0, p < 0.001) and highest at the 4th visit. Sleep latency was longer as pregnancy progressed (18.5 mins to 23.2 mins, p = 0.001). Sleep duration became shorter over time and was the shortest at the 4th visit (7.1 h to 6.5 h, p < 0.001). Sleep efficiency was the lowest at the 4th visit (85.2 to 81.6%, p < 0.001). The same trend was observed for subjects in different BMI groups throughput pregnancy. PSQI score increased and sleep duration decreased as BMI increased. The effect of increasing BMI on PSQI and sleep duration was only observed in the higher BMI groups (> 25 kg/m 2 )., Conclusions: Our study showed that sleep quality gradually declined throughout pregnancy for all BMI groups. Higher BMI was associated with poorer sleep as represented by PSQI score and sleep duration, particularly in the overweight and obese subgroups., (© 2022. The Author(s).)

Objective: To evaluate the safety in the first 12 h, efficacy and maternal satisfaction of a double balloon catheter (DBC) with vaginal prostaglandin (PGE) for induction of labour (IOL)., Methods: We conducted a multicentre randomised controlled study of 420 patients from 1st January 2016 to 31st December 2017 to evaluate the use of DBC in IOL in an Asian population looking at the adverse effects in the first 12 h after insertion. Women were assigned randomly to cervical ripening with either a DBC or a prostaglandin pessary. The adverse events in the 12 h after DBC or first prostaglandin inserted, the efficacy of a DBC to a prostaglandin in labour induction and maternal satisfaction were evaluated., Results: There were significantly less women with uterine hyperstimulation in the DBC (2 vs 24, p ≤ 0.0001) compared to the prostaglandin group. There were no women with uterine hyperstimulation and non-reassuring foetal status in the DBC while there were 5 women with uterine hyperstimulation and foetal distress in the prostaglandin group. Use of entonox was significantly less in the DBC group (p = 0.009). There were no significant differences in both groups in caesarean section, vaginal deliveries and time to delivery, although significant less time was needed to achieve cervical os dilation more than 4 cm in the DBC group (p ≤ 0.0001). Neonatal birth outcomes were similar. Women's pain scores were similar for both methods. 80.1% of women allocated the DBC and 76.8% of women allocated the PGE were keen to recommend their method of induction., Conclusion: Double balloon catheter remains a good alternative method for inducing women in view of a good safety profile with low risk of hyperstimulation and high maternal satisfaction., Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02620215., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: To compare the efficacy and safety of dinoprostone vaginal insert (DVI) alone versus DVI with adjunctive sweeping of membranes (ASM) for induction of labor (IOL)., Methods: Single-center, prospective, randomized controlled trial; women with singleton term pregnancies, cervical dilation ≥1 and <3 cm, intact membranes allocated to either DVI or DVI with ASM. The primary outcome was vaginal delivery within 24 h of insertion. Secondary outcomes included mean time from insertion to delivery, tachysystole, operative delivery for non-reassuring fetal status (NRFS), tocolytics, fetal outcomes, pain information, and subject satisfaction., Results: One hundred and four received DVI (Group 1) alone and 104 DVI with ASM (Group 2). The rate of vaginal delivery within 24 h was 53% versus 56%, cesarean rate 8.7% versus 10.6% in Groups 1 and 2 respectively. Although the duration of labor was similar in both groups, about 6% of women required additional ripening with dinoprostone vaginal tablets in Group 2 compared to 11.5% in Group 1 (p-value = 0.2). The frequency of hyperstimulation syndrome, failed induction, analgesic requirements, and fetal outcomes were comparable. The majority (83%-86%) in either cohort were satisfied with their labor experience. Multivariate logistic regression demonstrated a slightly better chance for vaginal delivery within 24 h (odds ratio [OR] 1.22 [95% confidence interval, CI 0.65-2.29]; p-value 0.53] for DVI with ASM, although statistically insignificant. Younger maternal age and multiparity (OR 10.36 [95% CI 4.88-23.67]; p-value <0.0001) contributed to successful IOL., Conclusion: DVI with ASM is at least as efficacious as DVI for cervical ripening with no increase in morbidity. Although DVI with ASM group less often needed additional dinoprostone tablets to complete the process of IOL (p-value = 0.2), adjunctive sweeping has not been shown to have a significant impact on the duration of labor or mode of delivery., (© 2021 The Authors. Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

Respiratory failure is the leading cause of death in patients with severe SARS-CoV-2 infection 1,2 , but the host response at the lung tissue level is poorly understood. Here we performed single-nucleus RNA sequencing of about 116,000 nuclei from the lungs of nineteen individuals who died of COVID-19 and underwent rapid autopsy and seven control individuals. Integrated analyses identified substantial alterations in cellular composition, transcriptional cell states, and cell-to-cell interactions, thereby providing insight into the biology of lethal COVID-19. The lungs from individuals with COVID-19 were highly inflamed, with dense infiltration of aberrantly activated monocyte-derived macrophages and alveolar macrophages, but had impaired T cell responses. Monocyte/macrophage-derived interleukin-1β and epithelial cell-derived interleukin-6 were unique features of SARS-CoV-2 infection compared to other viral and bacterial causes of pneumonia. Alveolar type 2 cells adopted an inflammation-associated transient progenitor cell state and failed to undergo full transition into alveolar type 1 cells, resulting in impaired lung regeneration. Furthermore, we identified expansion of recently described CTHRC1 + pathological fibroblasts 3 contributing to rapidly ensuing pulmonary fibrosis in COVID-19. Inference of protein activity and ligand-receptor interactions identified putative drug targets to disrupt deleterious circuits. This atlas enables the dissection of lethal COVID-19, may inform our understanding of long-term complications of COVID-19 survivors, and provides an important resource for therapeutic development.

Tumor-specific elucidation of physical and functional oncoprotein interactions could improve tumorigenic mechanism characterization and therapeutic response prediction. Current interaction models and pathways, however, lack context specificity and are not oncoprotein specific. We introduce SigMaps as context-specific networks, comprising modulators, effectors and cognate binding-partners of a specific oncoprotein. SigMaps are reconstructed de novo by integrating diverse evidence sources-including protein structure, gene expression and mutational profiles-via the OncoSig machine learning framework. We first generated a KRAS-specific SigMap for lung adenocarcinoma, which recapitulated published KRAS biology, identified novel synthetic lethal proteins that were experimentally validated in three-dimensional spheroid models and established uncharacterized crosstalk with RAB/RHO. To show that OncoSig is generalizable, we first inferred SigMaps for the ten most mutated human oncoproteins and then for the full repertoire of 715 proteins in the COSMIC Cancer Gene Census. Taken together, these SigMaps show that the cell's regulatory and signaling architecture is highly tissue specific.

Despite considerable efforts, the mechanisms linking genomic alterations to the transcriptional identity of cancer cells remain elusive. Integrative genomic analysis, using a network-based approach, identified 407 master regulator (MR) proteins responsible for canalizing the genetics of individual samples from 20 cohorts in The Cancer Genome Atlas (TCGA) into 112 transcriptionally distinct tumor subtypes. MR proteins could be further organized into 24 pan-cancer, master regulator block modules (MRBs), each regulating key cancer hallmarks and predictive of patient outcome in multiple cohorts. Of all somatic alterations detected in each individual sample, >50% were predicted to induce aberrant MR activity, yielding insight into mechanisms linking tumor genetics and transcriptional identity and establishing non-oncogene dependencies. Genetic and pharmacological validation assays confirmed the predicted effect of upstream mutations and MR activity on downstream cellular identity and phenotype. Thus, co-analysis of mutational and gene expression profiles identified elusive subtypes and provided testable hypothesis for mechanisms mediating the effect of genetic alterations., Competing Interests: Declaration of interests A.C. is founder, equity holder, consultant, and director of DarwinHealth Inc., a company that has licensed some of the algorithms used in this manuscript from Columbia University. M.J.A. is Chief Scientific Officer and equity holder at DarwinHealth, Inc. Patent 10,790,040, titled “Virtual Inference of Protein Activity by Regulon Analysis” has issued on Sept. 29, 2020 related to the VIPER method. Columbia University is also an equity holder in DarwinHealth Inc., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Pregnant women are reported to be at increased risk of severe coronavirus disease 2019 (COVID-19) due to underlying immunosuppression during pregnancy. However, the clinical course of COVID-19 in pregnancy and risk of vertical and horizontal transmission remain relatively unknown. We aim to describe and evaluate outcomes in pregnant women with COVID-19 in Singapore., Methods: Prospective observational study of 16 pregnant patients admitted for COVID-19 to 4 tertiary hospitals in Singapore. Outcomes included severe disease, pregnancy loss, and vertical and horizontal transmission., Results: Of the 16 patients, 37.5%, 43.8% and 18.7% were infected in the first, second and third trimesters, respectively. Two gravidas aged ≥35 years (12.5%) developed severe pneumonia; one patient (body mass index 32.9kg/m2) required transfer to intensive care. The median duration of acute infection was 19 days; one patient remained reverse transcription polymerase chain reaction (RT-PCR) positive >11 weeks from diagnosis. There were no maternal mortalities. Five pregnancies produced term live-births while 2 spontaneous miscarriages occurred at 11 and 23 weeks. RT-PCR of breast milk and maternal and neonatal samples taken at birth were negative; placenta and cord histology showed non-specific inflammation; and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulins were elevated in paired maternal and umbilical cord blood (n=5)., Conclusion: The majority of COVID-19 infected pregnant women had mild disease and only 2 women with risk factors (obesity, older age) had severe infection; this represents a slightly higher incidence than observed in age-matched non-pregnant women. Among the women who delivered, there was no definitive evidence of mother-to-child transmission via breast milk or placenta.

In contrast to fossorial and above-ground organisms, subterranean species have adapted to the extreme stresses of living underground. We analyzed the predicted protein-protein interactions (PPIs) of all gene products, including those of stress-response genes, among nine subterranean, ten fossorial, and 13 aboveground species. We considered 10,314 unique orthologous protein families and constructed 5,879,879 PPIs in all organisms using ChiPPI. We found strong association between PPI network modulation and adaptation to specific habitats, noting that mutations in genes and changes in protein sequences were not linked directly with niche adaptation in the organisms sampled. Thus, orthologous hypoxia, heat-shock, and circadian clock proteins were found to cluster according to habitat, based on PPIs rather than on sequence similarities. Curiously, "ordered" domains were preserved in aboveground species, while "disordered" domains were conserved in subterranean organisms, and confirmed for proteins in DistProt database. Furthermore, proteins with disordered regions were found to adopt significantly less optimal codon usage in subterranean species than in fossorial and above-ground species. These findings reveal design principles of protein networks by means of alterations in protein domains, thus providing insight into deep mechanisms of evolutionary adaptation, generally, and particularly of species to underground living and other confined habitats.

The WHO declared the coronavirus disease 2019 (COVID-19) a global pandemic on 11 March 2020. Lessons from SARS epidemic led Singapore to develop stringent infection control protocols in preparation for future pandemics. However, unlike SARS, COVID-19 appears to be more transmissible and is predicted to continue for longer. As of 14 June 2020, there have been 40,197 positive cases with 26 deaths in Singapore, and KK Women's and Children's Hospital (KKH) has managed a total of 73 cases. Obstetrics ultrasound is an indispensable medical service and must continue to operate during a pandemic. A key balance must be struck between keeping patients and healthcare workers safe while being able to provide quality and prompt obstetric care. Our Antenatal Diagnostic Centre (ADC) in KKH developed new strategies to adapt to the pandemic when the national Disease Outbreak Response System Condition (DORSCON) was raised from yellow to orange on 7 February 2020. In this paper, we discuss our clinical workflow to reduce the risk of transmission amongst patients and staff while minimising disruption to our services.

Introduction: To assess the level of anxiety and knowledge regarding COVID-19 amongst antenatal women., Materials and Methods: This cross-sectional survey was conducted in the antenatal clinics of KK Women's and Children's Hospital, Singapore, from 31 March to 25 April 2020 to assess pregnant women's knowledge of COVID-19, their perceptions of its impact upon pregnancy and psychological impact using the validated Depression, Anxiety, and Stress Scales (DASS-21)., Results: Of the 324 women who participated in the study, the mean age was 31.8 years (range, 20-45). The majority (53.7%) were multiparous with mean gestational age of 23.4 weeks (SD 10). The commonest sources of information were Internet-based social media platforms. A significant proportion were unaware, or associated COVID-19 infection during pregnancy with fetal distress (82.1%), intrauterine death (71.3%), fetal anomalies (69.8%), miscarriages (64.8%), preterm labour (67.9%) and rupture of membranes (61.4%). A total of 116 (35.8%) women screened positive for anxiety, 59 (18.2%) for depression, and 36 (11.1%) for stress. There was a significant association between household size and stress scores [B = 0.0454 (95% CI, 0.0035-0.0873)]. Women who associated COVID-19 infection with fetal anomalies and intrauterine fetal death had significantly higher anxiety scores [B = -0.395 (95% CI, -0.660 to -0.130) and B = -0.291 (95% CI, -0.562 to -0.021) respectively]., Conclusion: Our study highlights that a lack of timely and reliable information on the impact of COVID-19 on pregnancy and its outcomes results in increased levels of depression, anxiety and stress. The healthcare provider must address these issues urgently by providing evidence-based information using Internet-based resources and psychological support.

The significance of metabolic pathway prediction is to envision the viable unknown transformations that can occur provided the appropriate enzymes are present. It can facilitate the prediction of the consequences of host-pathogen interactions. In this article, we have proposed a new algorithm Architectural Similarity-based Automated Pathway Prediction (ASAPP) to predict metabolic pathways based on the structural similarity among the metabolites. ASAPP takes two-dimensional structure and molecular weight of metabolites as input, and generates a list of probable transformations without the knowledge of any externally established reactions, with an accuracy of 85.09 percent. ASAPP has also been applied to predict the outcome of pathogen liberated toxins on the carbohydrate and lipid pathways of the hosts. We have analyzed the disruption of host pathways in the presence of toxins, and have found that some metabolites in Glycolysis and the TCA cycle have a high chance of being the breakpoints in the pathway. The tool is available at http://asapp.droppages.com/.

Background: Effector proteins of bacteria infect their hosts by specific dedicated machinery identified as secretion systems. Currently, no mechanism to identify the effector proteins based on their 3D structure has been reported in the literature. In order to identify effector proteins, extraction of features from their 3D structure is crucial. However, effector protein datasets are highly imbalanced. State-of-the-art oversampling algorithms are incapable of dealing with such datasets. They usually eliminate samples as noise. They do not ensure generation of synthetic samples strictly in the vicinity of the minority class samples. In effector protein datasets, deletion of any samples as noise would lead to loss of crucial information. Furthermore, generation of synthetic samples of the minority class in the vicinity of majority class samples would lead to an inept classifier., Method: In this paper, we introduce an algorithm called Cluster Quality based Non-Reductional (CQNR) oversampling technique. Its novelty lies in generating new samples proportional to the distribution of samples of the minority classes, without eliminating any sample as noise. Utilizing CQNR, we develop a novel Effector Protein Predictor based on the 3D (EPP3D) structure of proteins. EPP3D is trained on a feature set, balanced by CQNR, comprising 3D structure-based features, namely, convex hull layer count, surface atom composition, radius of gyration, packing density and compactness, derived from the 3D structure of the experimentally verified effector proteins., Result: Fscore and Gmean demonstrate that CQNR has outperformed some well-established oversampling methods by approximately 3-5%, with respect to classification accuracy, on five benchmark datasets and three other highly imbalanced synthetically generated datasets. Likewise, for classification of pathogenic effector proteins, a significant improvement of 7-9% in accuracy has been noticed, on the application of CQNR followed by EPP3D. Moreover, EPP3D has exhibited an improvement of 2-4% in classifying effector proteins based on their 3D structure compared to the classification of effector proteins based on their amino acid sequences. The software for CQNR and EPP3D are available at http://projectphd.droppages.com/CQNR.html., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Tailored therapy aims to cure cancer patients effectively and safely, based on the complex interactions between patients' genomic features, disease pathology and drug metabolism. Thus, the continual increase in scientific literature drives the need for efficient methods of data mining to improve the extraction of useful information from texts based on patients' genomic features. An important application of text mining to tailored therapy in cancer encompasses the use of mutations and cancer fusion genes as moieties that change patients' cellular networks to develop cancer, and also affect drug metabolism. Fusion proteins, which are derived from the slippage of two parental genes, are produced in cancer by chromosomal aberrations and trans-splicing. Given that the two parental proteins for predicted fusion proteins are known, we used our previously developed method for identifying chimeric protein-protein interactions (ChiPPIs) associated with the fusion proteins. Here, we present a validation approach that receives fusion proteins of interest, predicts their cellular network alterations by ChiPPI and validates them by our new method, ProtFus, using an online literature search. This process resulted in a set of 358 fusion proteins and their corresponding protein interactions, as a training set for a Naïve Bayes classifier, to identify predicted fusion proteins that have reliable evidence in the literature and that were confirmed experimentally. Next, for a test group of 1817 fusion proteins, we were able to identify from the literature 2908 PPIs in total, across 18 cancer types. The described method, ProtFus, can be used for screening the literature to identify unique cases of fusion proteins and their PPIs, as means of studying alterations of protein networks in cancers. Availability: http://protfus.md.biu.ac.il/., Competing Interests: The authors have declared that no competing interests exist.

Objective: To design and examine the feasibility of a sustainable training program to build local capacity and improve obstetric outcomes in Kampong Chhnang, Cambodia., Methods: A "train-the-trainers" model was used to conduct an obstetrics course between 2012 and 2015, its aim to reduce maternal mortality and morbidity. All Cambodian healthcare providers trained by the program were included in the study. The obstetric outcomes of all patients under the care of the trained healthcare providers were analyzed retrospectively to assess the feasibility of the program. Data from all three hospitals and 42 health centers in the province that the trainees worked at were collected from case logs., Results: There was a significant increased trend in recognition of cases of postpartum hemorrhage and pre-eclampsia, and occurrence of difficult deliveries and cesarean deliveries (P<0.001). The maternal mortality ratio decreased from 64.7 per 100 000 deliveries in 2012 to 40.8 per 100 000 deliveries in 2016., Conclusion: This sustainable model has the potential to positively impact obstetric education and maternal outcomes and could be adopted in other resource-poor countries, particularly in Southeast Asia., (© 2019 International Federation of Gynecology and Obstetrics.)

Animals living at high altitudes have evolved distinct phenotypic and genotypic adaptations against stressful environments. We studied the adaptive patterns of altitudinal stresses on transcriptome turnover in subterranean plateau zokors (Myospalax baileyi) in the high-altitude Qinghai-Tibetan Plateau. Transcriptomes of zokors from three populations with distinct altitudes and ecologies (Low: 2846 m, Middle: 3282 m, High: 3,714 m) were sequenced and compared. Phylogenetic and principal component analyses classified them into three divergent altitudinal population clusters. Genetic polymorphisms showed that the population at H, approaching the uppermost species boundary, harbors the highest genetic polymorphism. Moreover, 1056 highly up-regulated UniGenes were identified from M to H. Gene ontologies reveal genes like EPAS1 and COX1 were overexpressed under hypoxia conditions. EPAS1, EGLN1, and COX1 were convergent in high-altitude adaptation against stresses in other species. The fixation indices (F ST and G ST )-based outlier analysis identified 191 and 211 genes, highly differentiated among L, M, and H. We observed adaptive transcriptome changes in Myospalax baileyi, across a few hundred meters, near the uppermost species boundary, regardless of their relatively stable underground burrows' microclimate. The highly variant genes identified in Myospalax were involved in hypoxia tolerance, hypercapnia tolerance, ATP-pathway energetics, and temperature changes.

Objective: Antenatal corticosteroids before preterm births are considered to be most effective 48 h after and up to 1 week after the first dose. We aim to evaluate: (1) our practice of administration of antenatal corticosteroids in Singapore; (2) admission characteristics of women for discriminatory factors of spontaneous preterm delivery within 1 week., Methods: This is a retrospective study in a tertiary obstetrics unit in Singapore. 3044 women who delivered live births (at term or preterm) from 1st November 2014 to 31st January 2015, who were at risk of spontaneous or induced preterm delivery, were included. Data related to the time of and indications for antenatal corticosteroids administration, characteristics assessed at the time of presentation, and time of delivery were collected and analysed., Results: 85.9% of women who delivered at gestational age ≤ 34 +6 received at least one dose. 22.1% had delivered within the window of efficacy. Gestational age > 32 weeks at presentation, uterine activity on tocography and cervical dilation with effacement were associated with preterm delivery within 1 week of presentation., Conclusion: Overall, our antenatal corticosteroids administration rate is comparable to that attained by centres in other developed countries. It is difficult but important to discriminate women who will benefit from this timely intervention.

The aim of this study was to investigate the efficacy of the Bakri balloon in the management of PPH. This was a retrospective review of 49 patients, who had Bakri balloon inserted for PPH in KK Hospital between April 2013 and December 2015. The main outcome measure was achievement of haemostasis by Bakri balloon tamponade (BBT). Our success rate was 81.6%. Out of the nine failures (18.0%), five (55.6%) had subtotal hysterectomies and four (44.4%) had total hysterectomies. The causes of PPH in these nine women were unsuspected or foci of placenta accreta (55.6%), uterine atony (33.3%) and retained products of conception (11.1%). Our study suggests that BBT is more likely to fail when bleeding is secondary to undiagnosed focal placenta accreta (p = .011) and when the estimated blood loss is more than 1.5 litres (p < .001). Our study adds to the growing body of evidence that BBT is not only effective for management of PPH in haemodynamically stable patients and in cases secondary to uterine atony and placenta praevia, but also in a small number of undiagnosed focal placenta accreta. Impact statement There is limited evidence regarding efficacy of BBT for PPH. Our study supports the use of BBT for PPH due to uterine atony and placenta praevia and in a small number of undiagnosed placenta accreta.

Objective: Antenatal corticosteroid (ACS) has long been regarded as the standard of care for women at risk of preterm labour. There are, however, varying practices and regimes in ACS administration. It is unclear if "a window of efficacy" truly exists and if the benefits of ACS would diminish after 7 days from the first dose. The objective of this study is to determine if the time interval between antenatal corticosteroids and delivery influences the neonatal outcomes in preterm deliveries from 23 +5 to 36 +6 weeks' gestation., Methods: This is a retrospective analysis of 302 women and 352 infants who delivered from 23 +5 to 36 +6 weeks' gestation in KK Women's and Children's Hospital from 1st November 2014 to 31st January 2015. The timings of the first two doses of corticosteroids and the delivery were retrieved. Neonatal outcomes were compared between those delivering within 7 days and those delivering beyond 7 days of first dose of ACS., Results: 61.2% of preterm infants received at least one dose of antenatal corticosteroids, of which 23.6% received it within the window of efficacy. Overall incidence of respiratory distress asyndrome in our study is 17.6%. Significantly, neonates with ACS exposure beyond 7 days were seven times more likely to have RDS as compared to those exposed to ACS within the window of efficacy (RR 0.535, 95% CI 0.166-1.72), after adjusting for potential confounders., Conclusion: The results of this study support the current practice among obstetricians to aim to administer ACS within 7 days of delivery.

Enterococcus faecalis , a member of the human gastrointestinal microbiota, is an opportunistic pathogen associated with hospital-acquired wound, bloodstream, and urinary tract infections. E. faecalis can subvert or evade immune-mediated clearance, although the mechanisms are poorly understood. In this study, we examined E. faecalis -mediated subversion of macrophage activation. We observed that E. faecalis actively prevents NF-κB signaling in mouse RAW264.7 macrophages in the presence of Toll-like receptor agonists and during polymicrobial infection with Escherichia coli E. faecalis and E. coli coinfection in a mouse model of catheter-associated urinary tract infection (CAUTI) resulted in a suppressed macrophage transcriptional response in the bladder compared to that with E. coli infection alone. Finally, we demonstrated that coinoculation of E. faecalis with a commensal strain of E. coli into catheterized bladders significantly augmented E. coli CAUTI. Taken together, these results support the hypothesis that E. faecalis suppression of NF-κB-driven responses in macrophages promotes polymicrobial CAUTI pathogenesis, especially during coinfection with less virulent or commensal E. coli strains., (Copyright © 2017 American Society for Microbiology.)

Fusion proteins, comprising peptides deriving from the translation of two parental genes, are produced in cancer by chromosomal aberrations. The expressed fusion protein incorporates domains of both parental proteins. Using a methodology that treats discrete protein domains as binding sites for specific domains of interacting proteins, we have cataloged the protein interaction networks for 11 528 cancer fusions (ChiTaRS-3.1). Here, we present our novel method, chimeric protein-protein interactions (ChiPPI) that uses the domain-domain co-occurrence scores in order to identify preserved interactors of chimeric proteins. Mapping the influence of fusion proteins on cell metabolism and pathways reveals that ChiPPI networks often lose tumor suppressor proteins and gain oncoproteins. Furthermore, fusions often induce novel connections between non-interactors skewing interaction networks and signaling pathways. We compared fusion protein PPI networks in leukemia/lymphoma, sarcoma and solid tumors finding distinct enrichment patterns for each disease type. While certain pathways are enriched in all three diseases (Wnt, Notch and TGF β), there are distinct patterns for leukemia (EGFR signaling, DNA replication and CCKR signaling), for sarcoma (p53 pathway and CCKR signaling) and solid tumors (FGFR and EGFR signaling). Thus, the ChiPPI method represents a comprehensive tool for studying the anomaly of skewed cellular networks produced by fusion proteins in cancer., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Discovery of chimeric RNAs, which are produced by chromosomal translocations as well as the joining of exons from different genes by trans-splicing, has added a new level of complexity to our study and understanding of the transcriptome. The enhanced ChiTaRS-3.1 database (http://chitars.md.biu.ac.il) is designed to make widely accessible a wealth of mined data on chimeric RNAs, with easy-to-use analytical tools built-in. The database comprises 34 922: chimeric transcripts along with 11 714: cancer breakpoints. In this latest version, we have included multiple cross-references to GeneCards, iHop, PubMed, NCBI, Ensembl, OMIM, RefSeq and the Mitelman collection for every entry in the 'Full Collection'. In addition, for every chimera, we have added a predicted Chimeric Protein-Protein Interaction (ChiPPI) network, which allows for easy visualization of protein partners of both parental and fusion proteins for all human chimeras. The database contains a comprehensive annotation for 34 922: chimeric transcripts from eight organisms, and includes the manual annotation of 200 sense-antiSense (SaS) chimeras. The current improvements in the content and functionality to the ChiTaRS database make it a central resource for the study of chimeric transcripts and fusion proteins., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background and Aims: A decision-to-delivery interval (DDI) of 30 min for category-one caesarean section (CS) deliveries is the standard of practice recommended by clinical guidelines. Our institution established a protocol for category-one ('crash') CS to expedite deliveries. The aim of this study is to evaluate DDI, factors that affect DDI and the mode of anaesthesia for category-one CS., Methods: This retrospective cohort study evaluated 390 women who underwent category-one CS in a tertiary obstetric centre. We analysed the factors associated with DDI, mode of anaesthesia and perinatal outcomes. Summary statistics were performed for the outcomes. The association factors were considered significant at P < 0.05., Results: The mean (standard deviation) DDI was 9.4 (3.2) min with all deliveries achieved within 30 min. The longest factor in the DDI was time taken to transfer patients. A shorter DDI was not significantly associated with improved perinatal outcomes. The majority (88.9%) of women had general anaesthesia (GA) for category-one CS. Of those who had an epidural catheter already in situ (34.4%), 25.6% had successful epidural extension. GA was associated with shorter DDI, but worse perinatal outcomes than regional anaesthesia (RA)., Conclusions: Our 'crash' CS protocol achieved 100% of deliveries within 30 min. The majority (88.9%) of the patients had GA for category-one CS. GA was found to be associated with shorter anaesthesia and operation times, but poorer perinatal outcomes compared to RA.

Incipient sympatric speciation in blind mole rat, Spalax galili, in Israel, caused by sharp ecological divergence of abutting chalk-basalt ecologies, has been proposed previously based on mitochondrial and whole-genome nuclear DNA. Here, we present new evidence, including transcriptome, DNA editing, microRNA, and codon usage, substantiating earlier evidence for adaptive divergence in the abutting chalk and basalt populations. Genetic divergence, based on the previous and new evidence, is ongoing despite restricted gene flow between the two populations. The principal component analysis, neighbor-joining tree, and genetic structure analysis of the transcriptome clearly show the clustered divergent two mole rat populations. Gene-expression level analysis indicates that the population transcriptome divergence is displayed not only by soil divergence but also by sex. Gene ontology enrichment of the differentially expressed genes from the two abutting soil populations highlights reproductive isolation. Alternative splicing variation of the two abutting soil populations displays two distinct splicing patterns. L-shaped FST distribution indicates that the two populations have undergone divergence with gene flow. Transcriptome divergent genes highlight neurogenetics and nutrition characterizing the chalk population, and energetics, metabolism, musculature, and sensory perception characterizing the abutting basalt population. Remarkably, microRNAs also display divergence between the two populations. The GC content is significantly higher in chalk than in basalt, and stress-response genes mostly prefer nonoptimal codons. The multiple lines of evidence of ecological-genomic and genetic divergence highlight that natural selection overrules the gene flow between the two abutting populations, substantiating the sharp ecological chalk-basalt divergence driving sympatric speciation.

Background: Studying biochemical pathway evolution for diseases is a flourishing area of Systems Biology. Here, we study Type 1 Diabetes Mellitus (T1D), focusing on growth of glutamate, β-alanine, taurine and hypotaurine, and butanoate metabolisms involved in onset of GAD and INS genes in Homo sapiens with comparative analysis in non-obese diabetic Mus musculus, biobreeding Diabetes-prone Rattus norvegicus, Pan troglodytes, Oryctolagus cuniculus, Danio rerio and Drosophila melanogaster respectively., Methods: We propose an algorithm for growth analysis for four metabolic pathways involved in T1D. It has three modules, pattern finding, interaction identification and growth detection. The first module identifies patterns using Community structures using Hamming distances and the Tanimoto coefficient. We have performed functional analysis by representing patterns using ODEs, and identified Stoichiometric, Gradient and Jacobian matrices. The second module identifies interactions among patterns using cut-sets and network-partitioning by 'Divide-and-conquer'. The third module identifies functions of patterns using interactions, thereby highlighting their nature of growth., Results: We observed that metabolites that are genetically robust and resist alterations against stable state during evolution, account for emergence of a scale-free network., Discussion: New modules get acquired to the fundamental cluster in a preferential manner, an instance of micro-evolution theory. For instance, (S)-3-hydroxy butanoyl-CoA, acetoacetyl-CoA, acetoacetate, acetyl-CoA, (S)-3-hydroxy-3-methyl glutaryl-CoA acts as a fundamental cluster in butanoate metabolism. Moreover, the interactions among metabolites are divergent in nature., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Metabolomics is one of the key approaches of systems biology that consists of studying biochemical networks having a set of metabolites, enzymes, reactions and their interactions. As biological networks are very complex in nature, proper techniques and models need to be chosen for their better understanding and interpretation. One of the useful strategies in this regard is using path mining strategies and graph-theoretical approaches that help in building hypothetical models and perform quantitative analysis. Furthermore, they also contribute to analyzing topological parameters in metabolome networks. Path mining techniques can be based on grammars, keys, patterns and indexing. Moreover, they can also be used for modeling metabolome networks, finding structural similarities between metabolites, in-silico metabolic engineering, shortest path estimation and for various graph-based analysis. In this manuscript, we have highlighted some core and applied areas of path-mining for modeling and analysis of metabolic networks., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Disease Systems Biology is an area of life sciences, which is not very well understood to date. Analyzing infections and their spread in healthy metabolite networks can be one of the focussed areas in this regard. We have proposed a theory based on the classical forest fire model for analyzing the path of infection spread in healthy metabolic pathways. The theory suggests that when fire erupts in a forest, it spreads, and the surrounding trees also catch fire. Similarly, when we consider a metabolic network, the infection caused in the metabolites of the network spreads like a fire. We have constructed a simulation model which is used to study the infection caused in the metabolic networks from the start of infection, to spread and ultimately combating it. For implementation, we have used two approaches, first, based on quantitative strategies using ordinary differential equations and second, using graph-theory based properties. Furthermore, we are using certain probabilistic scores to complete this task and for interpreting the harm caused in the network, given by a 'critical value' to check whether the infection can be cured or not. We have tested our simulation model on metabolic pathways involved in Type I Diabetes mellitus in Homo sapiens. For validating our results biologically, we have used sensitivity analysis, both local and global, as well as for identifying the role of feedbacks in spreading infection in metabolic pathways. Moreover, information in literature has also been used to validate the results. The metabolic network datasets have been collected from the Kyoto Encyclopedia of Genes and Genomes (KEGG).

Introduction: This study aimed to assess maternal and perinatal outcomes following second stage Caesarean sections., Methods: A retrospective study was conducted in a Singapore-based tertiary referral centre from January 1, 2009 to December 31, 2009. The medical records of all the women who underwent emergency Caesarean sections in the second stage of labour were reviewed., Results: Out of 2,501 emergency Caesarean sections performed, 116 were Caesarean sections in the second stage of labour. Women with non-vertex, twins and preterm deliveries were excluded, and 110 (4.4%, 110/2,501) Caesarean sections were recruited. The majority of the Caesarean sections were determined and performed by registrars or consultants. With regard to maternal outcome, 2.7% (3/110) of patients had primary postpartum haemorrhage and 4.5% (5/110) of patients had vertical or lateral lower uterine segment tears. As for neonatal outcome, although the Apgar scores of newborns were low at birth for 8.2% (9/110) of patients, the Apgar score was > 4 at 5 minutes for all patients., Conclusion: Overall, there was no statistically significant adverse maternal or perinatal outcome.

Background: The article describes the experience of planning and implementing the transition of the residency program in obstetrics and gynecology at Singhealth, Singapore, from a model largely based on British training principles to a new model in accordance with the ACGME-International (ACGME-I) standards., Intervention: Initial steps in transitioning to the new model entailed (1) identifying faculty with an interest in education to lead the various initiatives and programs and to ensure appropriate educational role models, (2) securing adequate funding, (3) holding focus groups with physicians to identify opportunities for improvement in the new system, and (4) developing a schedule for the phased implementation of key features of the structured system., Results: The program started in July 2011, with 14 residents for a 4-year course of training. The curriculum consisted of 5 modules: (1) general obstetrics and gynecology and ambulatory care, (2) maternal fetal medicine, (3) urogynecology and minimally invasive surgery, (4) reproductive medicine, and (5) gynecology oncology. Faculty was assigned responsibility for teaching and assessing the 6 competencies, and appropriate training was provided through specially designed, professional-development programs., Conclusions: Challenges in the implementation of the new training program included the need to replace clinical service previously provided by trainees, a lack of fit between the traditional qualifying exam and the new model for training, and the need to adapt teaching strategies to new competencies not explicitly taught in the prior program, particularly practice-based learning and improvement and systems-based practice. The strength of the new obstetrics and gynecology residency lies in having a structured, competency-based, closely supervised approach to training with standardized evaluations, timely feedback, and a committed faculty.

In-silico metabolic engineering is a very useful branch of systems biology for modeling, analysis and prediction of various outcomes of metabolic pathways. It can also be used for detecting interactions and dynamics within a network. Various protocols have been proposed for modeling a pathway. But most of these protocols have various disadvantages and shortcomings with respect to automated pathway modeling and analysis. In the present article, we have proposed a novel algorithm for automated pathway reconstruction. We have also made a comparative study of our algorithm with other standard protocols and discussed its advantages over others. We present StructurAl Grammar-based automated PAthway Reconstruction (SAGPAR), a fast and robust algorithm that generates any metabolic pathway using some given structural representations of metabolites. Users can model any pathway based on some pre-required features that are asked as an input by the algorithm. The algorithm also takes into considerations various thermodynamic thresholds and structural properties while modeling a pathway. The given algorithm has been tested on the standard pathway datasets of 25 pathways of Mycoplasma pneumoniae M129 and 24 pathways of Homo sapiens. The dataset is taken from KEGG and PubChem Compound data repositories. SAGPAR performs much better than some already present metabolic pathway analysis tools like Copasi, PHT, Gepasi, Jarnac and Path-A.

Background: A complex network of biochemical reactions present in an organism generates various biological moieties necessary for its survival. It is seen that biological systems are robust to genetic and environmental changes at all levels of organization. Functions of various organisms are sustained against mutational changes by using alternative pathways. It is also seen that if any one of the paths for production of the same metabolite is hampered, an alternate path tries to overcome this defect and helps in combating the damage., Methodology: Certain physical, chemical or genetic change in any of the precursor substrate of a biochemical reaction may damage the production of the ultimate product. We employ a quantitative approach for simulating this phenomena of causing a physical change in the biochemical reactions by performing external perturbations to 12 metabolic pathways under carbohydrate metabolism in Saccharomyces cerevisae as well as 14 metabolic pathways under carbohydrate metabolism in Homo sapiens. Here, we investigate the relationship between structure and degree of compatibility of metabolites against external perturbations, i.e., robustness. Robustness can also be further used to identify the extent to which a metabolic pathway can resist a mutation event. Biological networks with a certain connectivity distribution may be very resilient to a particular attack but not to another. The goal of this work is to determine the exact boundary of network breakdown due to both random and targeted attack, thereby analyzing its robustness. We also find that compared to various non-standard models, metabolic networks are exceptionally robust. Here, we report the use of a 'Resilience-based' score for enumerating the concept of 'network-breakdown'. We also use this approach for analyzing metabolite essentiality providing insight into cellular robustness that can be further used for future drug development., Results: We have investigated the behavior of metabolic pathways under carbohydrate metabolism in S. cerevisae and H. sapiens against random and targeted attack. Both random as well as targeted resilience were calculated by formulating a measure, that we termed as 'Resilience score'. Datasets of metabolites were collected for 12 metabolic pathways belonging to carbohydrate metabolism in S. cerevisae and 14 metabolic pathways belonging to carbohydrate metabolism in H. sapiens from Kyoto Encyclopedia for Genes and Genomes (KEGG)., (Copyright © 2011 Elsevier Ltd. All rights reserved.)